AMR Current Practice Survey - North America

Marc Halushka MD, PhDJohns Hopkins University SOM

10th Banff Conference on Allograft PathologyAugust 12, 2009

DisclosuresNo Relevant Financial Relationships with

Commercial Interests & No Reference to an Unlabeled or Unapproved use of a Drug or

Product

Marc Halushka, MD, PhD

To understand the range of methods different institutions use to evaluate AMR.

To recognize the range of protocols different institutions have regarding evaluating AMR.

To realize that the time is upon us to develop a consensus guideline for AMR.

Objectives

Implementation of the ISHLT 2004 criteria

What centers doing regarding the evaluation of antibody-mediated (AMR/ humoral) rejection? (How much AMR are different groups reporting?)

Two Areas of Variability

Survey of pathologists at US and Canadian heart transplantation centers

Queried about use and comfort with the ISHLT 2004 criteria & AMR-related practices

Johns Hopkins Cardiac Transplantation Survey

Identified 113 US Centers and 9 Canadian Centers that performed heart transplantations in 2008 (UNOS and Dr. Veinot – U of Ottawa).

Identified one pathologist per institution who read cardiac transplantation biopsies (via websites, colleagues, phone calls to pathology departments/practices, etc).

Generated survey questions, placed these on SurveyMonkey and had the questions piloted by 4 cardiovascular pathology colleagues who assessed accuracy and coverage.

Survey was open from April 16, 2009 through May 20, 2009. Multiple reminder emails were sent, reminder phone calls were made and continuous updates made to reach the appropriate pathologists and maximize inclusion.

Survey Information

94 Respondents

• 78% of transplant centers

• 82% of all transplants in 2008 Represents a good cross-section of US

and Canadian centers

Survey Response

90% of centers reported evaluating for AMR.

Centers that did not evaluate tended to perform fewer biopsies per year but were otherwise similar to other centers.

Centers evaluating for AMR

Never Very Rarely (≤1%)

Rarely (2-5%)

Occasionally (6-10%)

Often (11-30%)

0

5

10

15

20

25

30

35

Prevalence of AMR as a percent of all transplant biopsies

Cou

nt o

f Cen

ters

1% 40% 40% 18% 2%

~20%~80%

Regional Variation in AMR% of Centers >5%

AMR levels

0%8%19%30-35%60%

No data from AK, DL, HI, ID, ME, MS, MT, ND, NH, NM, NV, RI, SD, UT, VT, WV, WY

All biopsies Limited biopsies0

10

20

30

40

50

60

Standard Protocols for Investigating AMR

25%

Cou

nt o

f Cen

ters

75%

Clinica

l Sus

picion

Sugge

stive

H&E

1st 3

mon

ths

1st y

ear

Cellula

r Reje

ction

PRAs

ABO Inco

mpatib

le0

10

20

30

40

50

Limited Protocols for Investigating AMR

62% 13% 4% 4%39% 3% 1%

Cou

nt o

f Cen

ters

Staining Protocols for AMR

C4d IH

C

C4d IFCD68

C3d IF IgG

IgM C3IgA

C1qCD31

Fibrin

Fibrinog

en

C3d IHC C4

HLA-D

R

Kappa

Lambd

a

Albumin

05

101520253035404550

C3d IF4%

C4d Both IF & IHC21%

C4d IF36%

C4d IHC39%

Cou

nt o

f Cen

ters

Association between staining protocol and AMR

C4d IHC C4d IF Both0%5%

10%15%20%25%30%35%40%

Cen

ters

repo

rting

>5%

AM

R

*

*OR = 3.15 p=0.05

“It would be good to know what the standard is for screening for AMR. It seems that by the time we are seeing positive IF (done only by request based on clinical suspicion), the clinical picture is so dire that the patients do not do well.”

“Criteria on when to automatically test for humoral rejection would be useful. We occasionally see staining of only a few capillaries or blood vessels with C4d. We comment on it, but it would be nice to have a standardized way of grading / handling C4d staining.”

“I have tried to assess humoral rejection and have found it impossible to interpret.”

Survey Comments

“The aspect of biopsy grading that needs further standardization is AMR. When you talk to colleagues at other institutions, everyone is doing something different - different indications, different techniques, different interpretation. The clinical side needs to be addressed as well. If we have positive C4d staining and the patient is fine, no one knows what to do.”

Survey Comments

Conclusions Prevalence of AMR: ~20% of centers report >5% of all biopsies have AMR. This varies regionally. Evaluation of AMR: 90% of transplant centers do evaluate – nearing consensus Protocol for AMR: 25% of centers evaluate every biopsy for AMR. Numerous other limited protocols exist. – need for consensus Staining for AMR: Wide variability in C4d staining protocols (IF, IHC, both). 60% of centers also stain for other proteins (immunoglobulins, etc) – need for consensus

AcknowledgementsJohns Hopkins University SOMLauren KucirkaJoseph MaleszewskiDorry Segev

94 Survey RespondentsChi LaiDylan MillerCharles SteenbergenCarmela TanJohn Veinot